Estrogen deficiency has been considered the seminal mechanism of osteoporosis in both women and men, but epidemiological evidence in humans and recent mechanistic studies in rodents indicate that ...aging and the associated increase in reactive oxygen species (ROS) are the proximal culprits. ROS greatly influence the generation and survival of osteoclasts, osteoblasts, and osteocytes. Moreover, oxidative defense by the FoxO transcription factors is indispensable for skeletal homeostasis at any age. Loss of estrogens or androgens decreases defense against oxidative stress in bone, and this accounts for the increased bone resorption associated with the acute loss of these hormones. ROS-activated FoxOs in early mesenchymal progenitors also divert ß-catenin away from Wnt signaling, leading to decreased osteoblastogenesis. This latter mechanism may be implicated in the pathogenesis of type 1 and 2 diabetes and ROS-mediated adverse effects of diabetes on bone formation. Attenuation of Wnt signaling by the activation of peroxisome proliferator-activated receptor γ by ligands generated from lipid oxidation also contributes to the age-dependent decrease in bone formation, suggesting a mechanistic explanation for the link between atherosclerosis and osteoporosis. Additionally, increased glucocorticoid production and sensitivity with advancing age decrease skeletal hydration and thereby increase skeletal fragility by attenuating the volume of the bone vasculature and interstitial fluid. This emerging evidence provides a paradigm shift from the “estrogen-centric” account of the pathogenesis of involutional osteoporosis to one in which age-related mechanisms intrinsic to bone and oxidative stress are protagonists and age-related changes in other organs and tissues, such as ovaries, accentuate them.
Increased oxidative stress is strongly implicated in the biology of aging and the pathogenesis of age-related diseases. Recent evidence indicates that oxidative stress is also a fundamental mechanism of the age-dependant decline of bone mass and strength and that loss of estrogens exaggerates the effects of aging on bone by decreasing defense against oxidative stress. Moreover, the balance between the generation of reactive oxygen species versus defense against them by FoxO-activated transcription programs is critical for bone homeostasis throughout life. Attenuation of Wnt signaling by PPARγ activation by oxidized lipids and an increase in endogenous glucocorticoids with age are two additional mechanisms contributing to skeletal involution. This new knowledge provides a paradigm shift from the traditional “estrogen-centric” account of the pathogenesis of osteoporosis to one in which aging per se is inexorably the protagonist.
About the Authors: Stavros C. Manolagas * E-mail: ManolagasStavros@uams.edu Affiliations Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of ...Arkansas for Medical Sciences, Arkansas, United States of America, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States of America ORCID logo http://orcid.org/0000-0002-0826-3484 Citation: Manolagas SC (2020) Osteocalcin promotes bone mineralization but is not a hormone. Examples are skeletal development, growth, adaptation of the skeleton to mechanical forces, fracture healing, changing calcium needs, stress, menstrual cycle, pregnancy, lactation, menopause, aging, hyperparathyroidism or hypoparathyroidism, hyperthyroidism, hypercortisolemia, Paget’s disease, bone tumors, etc. ...mouse gene targeting studies of GPRC6A, proposed to be an OCN receptor that modulates pancreatic β-cell proliferation 3, have yielded conflicting results with regard to glucose and energy metabolism 9–11. The mutant mice do, nonetheless, exhibit increased bone crystal size and maturation of hydroxyapatite, consistent with the aforementioned report of Moriishi and colleagues, earlier evidence by many other groups, and the general consensus that OCN plays a role in mineralization.
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Mouse models with cell-specific deletion of the estrogen receptor (ER) α, the androgen receptor (AR) or the receptor activator of nuclear factor κB ligand (RANKL), as well as cascade-selective ...estrogenic compounds have provided novel insights into the function and signalling of ERα and AR. The studies reveal that the effects of estrogens on trabecular versus cortical bone mass are mediated by direct effects on osteoclasts and osteoblasts, respectively. The protection of cortical bone mass by estrogens is mediated via ERα, using a non-nucleus-initiated mechanism. By contrast, the AR of mature osteoblasts is indispensable for the maintenance of trabecular bone mass in male mammals, but not required for the anabolic effects of androgens on cortical bone. Most unexpectedly, and independently of estrogens, ERα in osteoblast progenitors stimulates Wnt signalling and periosteal bone accrual in response to mechanical strain. RANKL expression in B lymphocytes, but not T lymphocytes, contributes to the loss of trabecular bone caused by estrogen deficiency. In this Review, we summarize this evidence and discuss its implications for understanding the regulation of trabecular and cortical bone mass; the integration of hormonal and mechanical signals; the relative importance of estrogens versus androgens in the male skeleton; and, finally, the pathogenesis and treatment of osteoporosis.
The cytokine receptor activator of nuclear factor kappa B ligand (RANKL), encoded by the Tnfsf11 gene, is essential for osteoclastogenesis and previous studies have shown that deletion of the Tnfsf11 ...gene using a Dmp1-Cre transgene reduces osteoclast formation in cancellous bone by more than 70%. However, the Dmp1-Cre transgene used in those studies leads to recombination in osteocytes, osteoblasts, and lining cells making it unclear whether one or more of these cell types produce the RANKL required for osteoclast formation in cancellous bone. Because osteoblasts, osteocytes, and lining cells have distinct locations and functions, distinguishing which of these cell types are sources of RANKL is essential for understanding the orchestration of bone remodeling. To distinguish between these possibilities, we have now created transgenic mice expressing the Cre recombinase under the control of regulatory elements of the Sost gene, which is expressed in osteocytes but not osteoblasts or lining cells in murine bone. Activity of the Sost-Cre transgene in osteocytes, but not osteoblast or lining cells, was confirmed by crossing Sost-Cre transgenic mice with tdTomato and R26R Cre-reporter mice, which express tdTomato fluorescent protein or LacZ, respectively, only in cells expressing the Cre recombinase or their descendants. Deletion of the Tnfsf11 gene in Sost-Cre mice led to a threefold decrease in osteoclast number in cancellous bone and increased cancellous bone mass, mimicking the skeletal phenotype of mice in which the Tnfsf11 gene was deleted using the Dmp1-Cre transgene. These results demonstrate that osteocytes, not osteoblasts or lining cells, are the main source of the RANKL required for osteoclast formation in remodeling cancellous bone.
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Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and ...androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably the landscape of our understanding of bone biology as well as the relationship between sex steroids and the physiology and pathophysiology of bone metabolism. Together with the appreciation of the side effects of estrogen-related therapies on breast cancer and cardiovascular diseases, these advances have also drastically altered the treatment of osteoporosis. In this article, we provide a comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on skeletal homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis. We highlight latest advances on the crosstalk between hormonal and mechanical signals, the relevance of the antioxidant properties of estrogens and androgens, the difference of their cellular targets in different bone envelopes, the role of estrogen deficiency in male osteoporosis, and the contribution of estrogen or androgen deficiency to the monomorphic effects of aging on skeletal involution.
Abstract Estrogens and androgens influence the growth and maintenance of bones and muscles and are responsible for their sexual dimorphism. A decline in their circulating levels leads to loss of mass ...and functional integrity in both tissues. In the article, we highlight the similarities of the molecular and cellular mechanisms of action of sex steroids in the two tissues; the commonality of a critical role of mechanical forces on tissue mass and function; emerging evidence for an interplay between mechanical forces and hormonal and growth factor signals in both bones and muscles; as well as the current state of evidence for or against a cross-talk between muscles and bone. In addition, we review evidence for the parallels in the development of osteoporosis and sarcopenia with advancing age and the potential common mechanisms responsible for the age-dependent involution of these two tissues. Lastly, we discuss the striking difference in the availability of several drug therapies for the prevention and treatment of osteoporosis, as compared to none for sarcopenia. This article is part of a Special Issue entitled “Muscle Bone Interactions”.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Major advances in understanding basic bone biology and the cellular and molecular mechanisms responsible for the development of osteoporosis, over the last 20 years, have dramatically ...altered the management of this disease. The purpose of this mini-review is to highlight the seminal role of Wnt signaling in bone homeostasis and disease and the emergence of novel osteoporosis therapies by targeting Wnt signaling with drugs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The Wnt/β-catenin signaling pathway affects several biological processes ranging from embryonic development, patterning, and postembryonic stem cell fate, to bone formation and insulin secretion in ...adulthood. β-Catenin mediates canonical Wnt signaling by binding to and activating members of the T-cell factor (TCF) transcription factor family. Similar to the Wnt/β-catenin pathway, oxidative stress influences fundamental cellular processes including stem cell fate and has been linked to aging and the development of age-related diseases. However, the molecular details of the pathogenetic effects of oxidative stress on the homeostasis of many different tissues remain unclear. β-Catenin has been recently implicated as a pivotal molecule in defense against oxidative stress by serving as a cofactor of the forkhead box O (FOXO) transcription factors. In addition, it has been shown that oxidative stress is a pivotal pathogenetic factor of age-related bone loss and strength in mice, leading to, among other changes, a decrease in osteoblast number and bone formation. These particular cellular changes evidently result from diversion of the limited pool of β-catenin from TCF- to FOXO-mediated transcription in osteoblastic cells. Fascinatingly, attenuation of Wnt-mediated transcription, resulting from an autosomal-dominant missense mutation in LRP6, a coreceptor for the Wnt-signaling pathway, has been linked recently genetically not only to premature osteoporosis, but also to coronary artery disease as well as several features of the metabolic syndrome including hyperlipidemia, hypertension, and diabetes, but not obesity. In this minireview, we highlight evidence linking the age-associated oxidative stress with FOXOs, Wnt/β-catenin signaling, osteoblastogenesis, adipogenesis, osteoporosis, and several features of the metabolic syndrome. We hypothesize that antagonism of Wnt signaling by oxidative stress with increasing age may be a common molecular mechanism contributing to the development not only of involutional osteoporosis, but several pathologies such as atherosclerosis, insulin resistance, and hyperlipidemia, all of which become more prevalent with advancing age.
This study examined bone-biopsy specimens obtained after a 3-year, double-blind, randomized, placebo-controlled, dose-ranging trial of oral alendronate to prevent bone resorption in healthy ...postmenopausal women. Long-term alendronate treatment was associated with an increase in the number of osteoclasts, which include distinctive giant, hypernucleated, detached osteoclasts that undergo protracted apoptosis. The finding of such cells, despite decreased resorption after long-term therapy with oral nitrogen-containing bisphosphonate, may have clinical implications.
In healthy postmenopausal women, long-term alendronate treatment was associated with an increase in the number of osteoclasts, which include distinctive giant, hypernucleated, detached osteoclasts that undergo protracted apoptosis.
Bisphosphonates are used worldwide to prevent fractures in patients with osteoporosis.
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Treatment with these drugs decreases the rate of bone resorption and levels of biochemical markers of bone turnover and causes progressive increases in bone mineral density. The clinical efficacy of nitrogen-containing bisphosphonates is widely believed to result from their potent ability to decrease the number of osteoclasts by promoting their apoptosis.
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Once osteoclasts become apoptotic, they are usually quickly ingested by bone marrow phagocytes.
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However, enumeration of osteoclasts in specimens of cancellous bone (bone composed of multiple trabecular structures) obtained from patients treated with nitrogen-containing bisphosphonates shows . . .
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